During the past FY, several labs have independently validated neuroprotection by p5 peptide after systemic i.p. injections or after AAV-9 delivery in animal models of PD and AD, respectively. In addition, p5 was shown to reduce the infarct size in an ischemic stroke model. These results confirm peptide efficacy and safety during applications that are short term, but dont address potential long-term safety issues. The safety of long-term systemic use of the peptide or focal peptide expression is critical before any clinical use. In fact, any potential detrimental effects of p5 on normal, synaptic Cdk5/p25 activity, which plays a role in LTD and neuroplasticity, must be ruled out. Evidence suggests that there are two types of Cdk5/p25 activities in neurons: normal synaptic and hyperactive cytoplasmic. Current evidence also suggests that p5 selectively reduces aberrant cytoplasmic Cdk5/p25 hyperactivity without interfering with synaptic plasticity. Using the LV vectors created by this lab to generate transgenic mice that express the secreted and cell-penetrating peptide in most cells would therefore be a very important step. The development of healthy transgenic mice, which express this new p5 peptide in every cell, behave normally and show normal cognition and motor functions, would be strong evidence for the safety of the peptide. These transgenic mice are an elegant solution to address key safety issues, while verifying therapeutic efficacy in various animal disease models. It is anticipated that these mice resist neurodegeneration and ameliorate associated immune responses. The p5 fragment of p35 is highly conserved in most lab animals and in human, and obtained results are relevant across these species. Even before extensive efficacy tests are started, it would be most cost-effective and less labor intensive to first generate these transgenic p5 mice to verify safety. Recent developments in non-toxic and non-immunocompromising conditioning methods in mice prior to hematopoietic stem cell transplantation are greatly encouraging, especially when viewed in combination with recently described methods for the generation of iPSCs that develop into all lymphoid and myeloid cell types. These stem cells could potentially be transplanted safely into older AD and PD populations. These future methodologies will advance safe and efficient targeted transgene delivery to the human CNS to sites of immunological responses during systemic CNS neurodegeneration.